An oft-quoted statistic in the field of biogerontology, the study of aging, is that slowing down the aging process would amount to a greater gain in lifespan than curing cancer, heart disease, stroke and diabetes today. Although this statistic is quite misleading, it underscores how important aging is to our general consciousness. Regardless of the desirability of slowing down aging, an understanding of the process of aging is an important stage in at least attempting to understand the human condition.
Aging is often defined as a stochastic, progressive and cumulative decline in function associated with higher mortality and lower reproductive capability that begins after reproductive maturity. Aging, however, is not manifested stochastically; individuals who age have discrete phenomenon such as an accelerated circadian rhythm or decreased neuronal conductance that occur across individuals. Aging is more aptly characterized as mechanistically stochastic, such that various forces, both external and internal combine to produce common phenomena in a random fashion. Further, the processes of aging, especially those of mutational accumulation, begin at birth, not after reproductive maturity.
Individuals intuitively conceive of aging as a physical phenomenon; the wear and tear of life eventually causes decline in function and death as is the case for cars. It would seem, however, that aging is not quite that simple. Although reactive oxygen species produced from cellular respiration do cause progressive damage in this manner, "genetic aging" is somewhat different. From both human and model organisms, it has been shown that genetic aging is related to structural integrity of the genome, not simply the genetic fidelity of the genome. So although mutations induced by free radicals and UV light are important, so are factors such as the status of telomeres, as well as acetylation patterns.
Of structural aberrations related to aging, telomere length has gotten the most attention. Telomeric repeats, or those on the ends of the chromosomes are progressively lost bit by bit in the natural process of many cycles of DNA replication, yet the enzyme telomerase restores these repeats to prevent the loss of genomic material. Further, short telomere length has been correlated with age-related disease and aged individuals. Additionally, cancer cells often have mechanisms of maintaining telomeres through increased or maintained expression of telomerase, providing a clue into how these cells might escape cellular aging.
Perhaps less well known is the story of histone acetylation in age progression. DNA is wound in proteins known as histones, which act as their gatekeepers. To gain access, the cell must acetylate these histones, allowing transcription of DNA to occur. However, to prevent transcription, these histones may have those acetyl groups removed by histone deacetylases. Interestingly, a known method of reducing the impact of aging, caloric restriction or undernourishment (not malnourishment), increases the expression of Sir2, a known histone deacetylase (Lin et al. Science 2000). Further, over-expression of Sir2 results in a longer lifespan in yeast (Guarente L Genes Dev 2000). This pattern of histone deacetylation in promoting longevity has been repeated for other proteins.
Although Sir2 acts at sites known to cause errors in transcription because they are heavily repetitive, the pattern of aging and chromatin stability seems to have broader implications. Studies in C. Elegans have demonstrated age-specific alterations in nuclear structure including chromatin structure (Haithcock et al. PNAS 2005). It would seem that genomic structural stability is quite important for maintenance of function and further that deacetylases play an important role in maintaining that stability. Perhaps the burst of gene expression associated with development cannot be tempered and results in phenomena such as accelerated circadian rhythms without compensated increased function in suppression mechanisms. Alternatively, it could be that histone deacetylases act specifically on areas of "error-prone" DNA allowing for greater longevity. In any event, it is clear that genomic structural stability is an important factor in aging.
Michael can be reached at michaelmcduffie@cavalierdaily.com.
Read More
Two senior U.Va. Health leaders quietly take new jobs without formal announcement
By Ford McCracken | YesterdayKibbe’s departure marks the end of an ongoing battle between U.Va. Health employees and their senior leadership.
Letter from 12 deans to Board of Visitors goes unanswered for almost two weeks
By Naima Sawaya | YesterdayAt the time of publication, the academic deans had received no response from the Board regarding their offer to meet with the Board “as soon as possible.”
Sen. Tim Kaine speaks to U.Va. students, discusses Ryan resignation and more
By Grace Traxler | 2 days agoIn an informal Q&A session, audience members asked about threats to federal research, the future of diversity, equity and inclusion at the University, potential shifts in the Democratic Party and more.
